Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial.

PURPOSE: Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors. METHODS: This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths. CONCLUSION: Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

Biomarker expression and survival in patients with non-small cell lung cancer receiving adjuvant chemotherapy in Denmark.

INTRODUCTION: Programmed cell death ligand-1 (PD-L1) expression may help identify patients with non-small cell lung cancer (NSCLC) who would benefit from immunotherapy. We assessed PD-L1 expression, and epidermal growth factor receptor (EGFR) and V-Ki-Ras2 Kirsten rat sarcoma (KRAS) mutations in NSCLC patients receiving adjuvant chemotherapy. METHODS: Data for stage IB/II/IIIA NSCLC patients (diagnosed: 2001-2012) were retrieved from Danish population-based registries. Tumor tissue samples were tested for PD-L1 expression using VENTANA PD-L1 (SP263) Assay in tumor cells (TC) at ≥25% cutoff and immune cells (IC) at ≥1% and ≥25% cutoffs. KRAS and EGFR mutations were tested using PCR-based assays. Follow-up began 120 days after diagnosis until death/emigration/January 1, 2015, whichever came first. Using Cox proportional hazard regression, hazard ratios (HRs) were computed for overall survival (OS) for each biomarker, adjusting for age, sex, histology, comorbidities, and tissue specimen age. RESULTS: Among 391 patients identified, 40.4% had stage IIIA disease, 49.9% stage II, and 8.7% stage IB. PD-L1-TC was observed in 38% of patients, EGFR mutations in 4%, and KRAS mutations in 29%. KRAS mutations were more frequent among patients with PD-L1 TC≥25% versus TC<25% (37% versus 24%). OS was not associated with PD-L1 TC≥25% versus TC<25% (stage II: adjusted HR = 1.15 [95% confidence interval: 0.66-2.01]; stage IIIA: 0.72 [0.44-1.19]). No significant association was observed with OS and PD-L1-IC ≥1% and ≥25%. EGFR and KRAS mutations were not associated with a prognostic impact. CONCLUSION: A prognostic impact for NSCLC patients receiving adjuvant chemotherapy was not associated with PD-L1 expression, or with EGFR and KRAS mutations.

NEPTUNE China cohort: First-line durvalumab plus tremelimumab in Chinese patients with metastatic non-small-cell lung cancer.

OBJECTIVES: The phase 3 NEPTUNE study (NCT02542293) evaluated first-line durvalumab plus tremelimumab (DT) versus chemotherapy for metastatic NSCLC. Prespecified exploratory analyses were conducted in an extended cohort enrolled in China. MATERIALS AND METHODS: Patients were randomized (1:1) to DT or standard chemotherapy, stratified by PD-L1 tumor cell (TC) expression (≥25 % vs < 25 %), histology, and smoking history. The primary analysis for this cohort was overall survival (OS) in patients with PD-L1 TC < 1 %. Secondary analyses included OS and progression-free survival (PFS) in the ITT population and PD-L1 subgroups, and safety. No alpha was allocated to these cohort analyses (data cut-off, 21-September-2020). RESULTS: 78 and 82 patients were randomized to DT and chemotherapy, respectively; 26 and 29 had PD-L1 TC < 1 % (median follow-up, 31.2 and 29.7 months [censored patients]). Among patients with PD-L1 TC < 1 %, OS favored DT versus chemotherapy (HR 0.60; 95 % CI, 0.32-1.11), with medians of 15.0 months (95 % CI, 10.5-27.4) and 11.7 months (95 % CI, 8.6-20.5), respectively; 24-month rates were 36.0 % (95 % CI, 18.2-54.2) and 17.9 % (95 % CI, 6.5-33.7). In the ITT population, OS was prolonged with DT versus chemotherapy (HR 0.70; 95 % CI, 0.48-1.02); medians were 20.0 and 14.1 months and 24-month rates were 44.2 % and 30.4 %. PFS was similar in the PD-L1 TC < 1 % (HR 1.13; 95 % CI, 0.59-2.14) and ITT (HR 0.95; 95 % CI, 0.66-1.36) populations; 12-month rates were 15.6 % versus 11.3 % and 23.9 % versus 16.6 %. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 31.2 % with DT and 52.6 % with chemotherapy; 3.9 % versus 10.3 % discontinued due to TRAEs. CONCLUSIONS: In exploratory analyses, first-line DT showed a trend towards improved OS versus chemotherapy among Chinese patients in the PD-L1 TC < 1 % population and ITT population, with 24-month OS and 12-month PFS rates indicating benefit in survival curve tails. DT was well tolerated with no new safety signals.

Association between immune-mediated adverse events and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab and tremelimumab.

Purpose: Immune-mediated adverse events (imAEs) may be associated with response to immune checkpoint inhibitors. We assessed the relationship between imAE development and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab (anti-programmed cell death ligand-1 [PD-L1]) alone or in combination with tremelimumab (anti-cytotoxic T-lymphocyte-associated protein 4). Methods: The analysis used individual patient-level data from 307 and 310 patients in the monotherapy and combination arms of MYSTIC, respectively. We evaluated the association between treatment efficacy and development of imAEs using univariate and multivariate survival analyses. Using machine learning, we built a predictive model utilizing baseline clinical and laboratory features to identify patients at risk of developing imAEs and further evaluated patient survival based on a threshold index extracted from the model. Results: Patients who developed any grade of imAE had improved overall survival versus patients without (hazard ratio [HR] 0.51; 95% confidence interval [CI]: 0.41-0.62). imAE development was associated with improved overall survival (HR 0.54; 95% CI 0.44-0.66) in a multivariate Cox proportional hazard model considering patient demographic features and baseline characteristics. Higher odds of imAE development were observed (odds ratio 3.023; 95% CI: 1.56-5.83) in responders versus non-responders in patients treated with immunotherapy. Based on baseline characteristics, the random forest classification algorithm was used to formulate a predictive model to identify patients at increased risk of developing imAEs during treatment. Conclusion: Post-hoc exploratory analysis found that the efficacy of immunotherapy was improved in patients who developed on-treatment imAEs. This was independent of severity of imAEs or the need for steroid treatment, which is important in allowing patients to remain on treatment and derive optimal clinical benefit. Further research is warranted to establish the correlation between incidence of imAEs and efficacy in this patient population.

Interferon gamma expression and mortality in unselected cohorts of urothelial bladder cancer patients.

BACKGROUND: The role of interferon gamma (IFN-γ) expression in long-term survival has not been studied in patients with urinary bladder cancer (UBC). IFN-γ expression was characterized among various UBC patient cohorts to assess if IFN-γ status is associated with overall survival (OS). METHODS: A tumor-based IFN-γ gene signature was evaluated among adult UBC patients newly diagnosed between 2004 and 2017 from two hospital systems in New York. Patient cohorts included metastatic (stage IV or progressing to stage IV [MBC]), muscle-invasive (stages T2a to T4a [MIBC]), and non-muscle-invasive (carcinoma in situ or stages 0a, 0is, and I [NMIBC]) disease. Descriptive analyses were conducted comparing IFN-γ signature in the highest tertile to those in the lowest two tertiles. RESULTS: 234 patients with bladder cancer were evaluated (56 MBC, 38 MIBC, and 140 NMIBC). Median OS was only reached in the MIBC cohort for those with an IFN-γ signature in the lowest two tertiles (15.03 months [95% CI, 8.50-50.60]). Those with an IFN-γ signature in the highest tertile had a decreased risk of mortality in all cohorts indicating better survival, but this was statistically significant in only the MIBC cohort (adjusted HR = 0.09 [95% CI, 0.01-0.73]). CONCLUSION: IFN-γ signature status was associated with a decreased mortality risk in all cohorts, particularly MIBC, indicating that it may be a prognostic marker of survival in patients with UBC.

PD-L1 expression, EGFR and KRAS mutations and survival among stage III unresected non-small cell lung cancer patients: a Danish cohort study.

Programmed cell death receptor ligand-1 (PD-L1) expression, KRAS (KRASm) and EGFR (EGFRm) mutations may influence non-small cell lung cancer (NSCLC) prognosis. We aimed to evaluate PD-L1 expression, KRASm, and EGFRm and survival among stage III unresected NSCLC patients. Using Danish registries, we collected data on stage III unresected NSCLC patients diagnosed 2001-2012 and paraffin-embedded tumor tissue from pathology archives. We assessed PD-L1 expression in tumors and tumor-infiltrating immune cells (ICs) by immunohistochemistry ([Formula: see text] 1% threshold for PD-L1+). We genotyped KRAS and EGFR. Follow-up extended from 120 days post-diagnosis to death, emigration, or 31/12/2014. We computed median survival using Kaplan-Meier methods, and hazard ratios (HRs) using Cox regression associating the biomarkers with death, adjusting for confounders. Among 305 patients, 48% had adenocarcinoma; 38% squamous cell carcinoma. Forty-nine percent had PD-L1+ tumors-51% stage IIIA and 26% KRASm. Few (2%) patients had EGFRm. Median survival in months was 14.7 (95% CI = 11.8-17.9) and 13.4 (95% CI = 9.5-16.3) in PD-L1+ and PD-L1- tumors, respectively. KRASm was not associated with death (HR = 1.06, 95% CI = 0.74-1.51 versus wildtype). PD-L1+ tumors yielded a HR = 0.83 (95% CI = 0.63-1.10); PD-L1+ ICs a HR = 0.51 (95% CI = 0.39-0.68). Tumor expression of PD-L1 did not influence survival. PD-L1+ ICs may confer survival benefit in stage III unresected NSCLC patients.

Programmed cell death ligand-1 expression and survival in a cohort of patients with non-small cell lung cancer receiving first-line through third-line therapy in Denmark.

BACKGROUND: PD-L1 expression on tumor cells (TCs) or immune cells (ICs) may be used as a prognostic marker for survival in patients with NSCLC. We characterized PD-L1 expression on TCs or ICs in a patient cohort with NSCLC to determine associations between PD-L1 expression and overall survival (OS), according to EGFR and KRAS mutation status. METHODS: Danish patients aged >18 years diagnosed with NSCLC before 2014 on first- (N = 491), second- (N = 368), or third-line (N = 498) therapy were included. Data were extracted from population-based medical registries. Tumor samples from pathology archives were tested for biomarkers. High PD-L1 expression was defined as expression on ≥25 % of TCs or ICs based on first diagnostic biopsy or surgical resection. KRAS and EGFR mutation status were tested using PCR-based assays. Cox regression analysis was used to compute adjusted HRs and associated 95 % CIs. RESULTS: PD-L1 TC and IC ≥ 25 % were observed in 24.3 %-31.0 % and 11.7-14.7 % of patients, respectively. EGFR and KRAS mutations were detected in 4.7 %-8.8 % and 26.5 %-30.7 % of patients, respectively. PD-L1 TC ≥ 25 % was not associated with survival advantage in first- (HR = 0.96, 95 % CI: 0.75-1.22), second- (1.08, 0.81-1.42), or third-line (0.94, 0.74-1.20) therapy. PD-L1 IC ≥ 25 % was associated with survival advantage in second-line (HR = 0.56, 95 % CI: 0.36-0.86) and third-line (0.69, 0.49-0.97) but not first-line (1.00, 0.70-1.41) therapy. CONCLUSION: No association was observed between PD-L1 TC ≥ 25 % and OS in any therapy line. PD-L1 IC ≥ 25 % may confer survival benefit among some patients who reach second-line therapy.

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world.

BACKGROUND: Mutations in STK11 (STK11m) and frequently co-occurring KRAS mutations (KRASm/STK11m) are associated with poor survival in metastatic NSCLC (mNSCLC) immuno-oncology trials. There are limited data regarding the prognostic significance of these mutations in a real-world setting. METHODS: This retrospective cohort study analyzed de-identified electronic medical records from the Flatiron Clinico-Genomic database to identify patients with mNSCLC who had initiated first-line immunotherapy (IO; alone or in combination) or chemotherapy under routine care between January 1, 2013 and June 30, 2017. The primary objectives were to assess the prevalence of STK11m and KRASm/STK11m and to determine associations of these mutations with overall and progression-free survival (OS, PFS). RESULTS: Of 2407 patients with mNSCLC, STK11m and KRASm/STK11m were present in 13.6% and 6.5% of patients, respectively. Worse OS outcomes were observed in patients with STK11m versus STK11wt mNSCLC receiving IO (first-line, HR [95% CI], 1.4 [0.9-2.3; p = 0.1]; second-line [subset of first-line cohort], HR, 1.6 [1.3-2.0; p = 0.0002]) or chemotherapy (first-line, HR, 1.4 [1.2-1.6; p < 0.0001]); PFS outcomes showed similar trends. KRASm/STK11m double mutations were associated with worse OS and PFS outcomes versus KRASwt/STK11wt with IO and chemotherapy, similar to the single mutation (STK11m vs STK11wt) findings. CONCLUSIONS: This large observational genomic study among patients receiving routine care highlights the negative prognostic impact of STK11m in patients with mNSCLC treated with IO or chemotherapy. These results complement previous clinical trial data and provide further evidence in the real world of a patient population that would benefit from new treatment options.

Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study.

OBJECTIVES: In the phase III CASPIAN study, first-line durvalumab plus etoposide in combination with either cisplatin or carboplatin (EP) significantly improved overall survival (primary endpoint) versus EP alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) at the interim analysis. Here we report patient-reported outcomes (PROs). MATERIALS AND METHODS: Treatment-naïve patients with ES-SCLC received 4 cycles of durvalumab plus EP every 3 weeks followed by maintenance durvalumab every 4 weeks until progression, or up to 6 cycles of EP every 3 weeks. PROs, assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13), were prespecified secondary endpoints. Changes from baseline to disease progression or 12 months in prespecified key disease-related symptoms (cough, dyspnea, chest pain, fatigue, appetite loss) were analyzed with a mixed model for repeated measures. Time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization was analyzed. RESULTS: In the durvalumab plus EP and EP arms, 261 and 260 patients were PRO-evaluable. Patients in both arms experienced numerically reduced symptom burden over 12 months or until progression for key symptoms. For the improvements from baseline in appetite loss, the between-arm difference was statistically significant, favoring durvalumab plus EP (difference, -4.5; 99% CI: -9.04, -0.04; nominal p = 0.009). Patients experienced longer TTD with durvalumab plus EP versus EP for all symptoms (hazard ratio [95% CI] for key symptoms: cough 0.78 [0.600‒1.026]; dyspnea 0.79 [0.625‒1.006]; chest pain 0.76 [0.575‒0.996]; fatigue 0.82 [0.653‒1.027]; appetite loss 0.70 [0.542‒0.899]), functioning, and global health status/QoL. CONCLUSION: Addition of durvalumab to first-line EP maintained QoL and delayed worsening of patient-reported symptoms, functioning, and global health status/QoL compared with EP.

Design and Rationale for a Phase III, Randomized, Placebo-controlled Trial of Durvalumab With or Without Tremelimumab After Concurrent Chemoradiotherapy for Patients With Limited-stage Small-cell Lung Cancer: The ADRIATIC Study.

Limited-stage (LS) small-cell lung cancer (SCLC) remains an area of high unmet medical need. The standard-of-care therapy comprises curative-intent platinum-based chemotherapy with concurrent radiotherapy (cCRT), which can be followed by prophylactic brain irradiation and then observation. However, most patients will relapse. Durvalumab (antiprogrammed cell death ligand-1) has enhanced the efficacy outcomes after cCRT for patients with unresectable, stage III non-small-cell lung cancer. Recently, durvalumab combined with platinum-etoposide demonstrated a significant survival benefit compared with platinum-etoposide as first-line treatment of patients with extensive-stage SCLC and has also shown antitumor activity as monotherapy and combined with tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4) in pretreated patients with extensive-stage SCLC. ADRIATIC, a phase III, randomized, double-blind, placebo-controlled, multicenter, global study (ClinicalTrials.gov identifier, NCT03703297), is designed to investigate the efficacy of durvalumab, with or without tremelimumab, as consolidation therapy for patients with LS-SCLC without disease progression after cCRT. Approximately 600 patients with documented histologic or cytologic LS-SCLC, World Health Organization/Eastern Cooperative Oncology Group performance status 0 or 1, and no progression after 4 cycles of cCRT will be randomized (1:1:1) to treatment (durvalumab 1500 mg plus placebo every 4 weeks [q4w] for 4 cycles, followed by durvalumab 1500 mg q4w; durvalumab 1500 mg plus tremelimumab 75 mg q4w for 4 cycles, followed by durvalumab 1500 mg q4w; or dual placebo q4w for 4 cycles, followed by single placebo q4w) within 1 to 42 days of completing cCRT, stratified by stage and receipt of prophylactic brain irradiation. The primary endpoints are progression-free survival and overall survival. The secondary endpoints are overall survival and progression-free survival rates, objective response rate, and safety and tolerability. Recruitment began in September 2018.

Fine-Needle Aspiration for the Evaluation of Hepatic Pharmacokinetics of Vaniprevir: A Randomized Trial in Patients With Hepatitis C Virus Infection.

Fine-needle aspiration (FNA) for serial hepatic sampling may be an efficient and less invasive alternative to core needle biopsy (CNB), the current standard for liver tissue sampling. In this randomized, open-label trial in 31 participants with hepatitis C virus genotype 1 infection (NCT01678131/Merck protocol PN048), we evaluated the feasibility of using FNA to obtain human liver tissue samples appropriate for measuring hepatic pharmacokinetics (PK), using vaniprevir as a tool compound. The primary end point was successful retrieval of liver tissue specimens with measurable vaniprevir concentrations at two of three specified FNA time points. Twenty-nine patients met the primary end point and, therefore, were included in the PK analyses. Hepatic vaniprevir concentrations obtained with FNA were consistent with known vaniprevir PK properties. The shape of liver FNA and CNB concentration-time profiles were comparable. In conclusion, FNA may be effective for serial tissue sampling to assess hepatic drug exposure in patients with liver disease.

A Molecular Epidemiological Analysis Of Programmed Cell Death Ligand-1 (PD-L1) Protein Expression, Mutations And Survival In Non-Small Cell Lung Cancer.

PURPOSE: To characterize programmed cell death ligand-1 (PD-L1) expression in relation to survival and gene mutation status in patients with advanced NSCLC. The study also explored the influence of tumor mutational burden (TMB) on PD-L1 expression and patient characteristics. PATIENTS AND METHODS: Adult patients with histologically or cytologically documented Stage IIIB/Stage IV/recurrent/progressive NSCLC, Eastern Cooperative Oncology Group performance status 0 to 3, and >2 lines of prior systemic treatment regimens were included in this retrospective analysis. Patients were treated from 1997 to 2015 at H. Lee Moffitt Cancer Center and Research Institute, Tampa, or at 7 community centers across the United States. PD-L1 expression level was determined using the VENTANA PD-L1 (SP263) Assay. EGFR and KRAS mutation status and ALK rearrangements were determined by targeted DNA sequencing; these were obtained from clinical records where targeted DNA sequencing was not performed. TMB was calculated as the total number of somatic mutations per sample. RESULTS: From a total of 136 patients included in the study, 23.5% had tumors with high PD-L1 expression (≥25%). There were no significant differences in patient characteristics, overall survival (OS), and progression-free survival (PFS) between patients with high PD-L1 expression (median OS: 39.5 months; median PFS: 15.8 months) vs low PD-L1 expression (<25%; median OS: 38.1 months; median PFS: 18.6 months). PD-L1 expression level correlated (P=0.05) with TMB and was consistent with The Cancer Genome Atlas data. CONCLUSION: In this retrospective analysis, survival outcomes of patients with advanced NSCLC were comparable by PD-L1 expression level. EGFR and KRAS mutation status were not found to be significantly associated with PD-L1 expression level, while TMB was weakly associated with PD-L1 expression level. Overall, PD-L1 expression level was not observed to be an independent prognostic biomarker in this cohort of patients with advanced NSCLC treated with chemotherapy.

SUPREME-HN: a retrospective biomarker study assessing the prognostic value of PD-L1 expression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Programmed cell death ligand-1 (PD-L1) expression on tumor cells (TCs) is associated with improved survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy, although its role as a prognostic factor is controversial. This study investigates whether tumoral expression of PD-L1 is a prognostic marker in patients with recurrent and/or metastatic (R/M) HNSCC treated with standard chemotherapy. METHODS: This retrospective, multicenter, noninterventional study assessed PD-L1 expression on archival R/M HNSCC tissue samples using the VENTANA PD-L1 (SP263) Assay. PD-L1 high was defined as PD-L1 staining of ≥ 25% TC, with exploratory scoring at TC ≥ 10% and TC ≥ 50%. The primary objective of this study was to estimate the prognostic value of PD-L1 status in terms of overall survival (OS) in patients with R/M HNSCC. RESULTS: 412 patients (median age, 62.0 years; 79.9% male; 88.2% Caucasian) were included from 19 sites in seven countries. 132 patients (32.0%) had TC ≥ 25% PD-L1 expression; 199 patients (48.3%) and 85 patients (20.6%) had TC ≥ 10% and ≥ 50%, respectively. OS did not differ significantly across PD-L1 expression (at TC ≥ 25% cutoff median OS: 8.2 months vs TC < 25%, 10.1 months, P = 0.55) or the ≥ 10% and ≥ 50% cutoffs (at TC ≥ 10%, median OS: 9.6 months vs TC < 10%, 9.4 months, P = 0.32, and at TC ≥ 50%, median OS 7.9 vs TC < 50%, 10.0 months, P = 0.39, respectively). CONCLUSIONS: PD-L1 expression, assessed using the VENTANA PD-L1 (SP263) Assay, was not prognostic of OS in patients with R/M HNSCC treated with standard of care chemotherapies. Trial registration ClinicalTrials.gov, NCT02543476. Registered September 4, 2015.

Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC. METHODS: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. FINDINGS: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. INTERPRETATION: First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. FUNDING: AstraZeneca.

HBV and HIV/HBV Infected Patients Have Distinct Immune Exhaustion and Apoptotic Serum Biomarker Profiles.

BACKGROUND: Hepatitis B virus (HBV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Due to their shared routes of transmission, approximately 10% of HIV-infected patients worldwide are chronically coinfected with HBV. Additionally, liver disease has become a major cause of morbidity and mortality in HBV/HIV coinfected patients due to prolonged survival with the success of antiretroviral therapy. The relationship between immune exhaustion markers (PD-1/PD-L1) and apoptotic markers such as Fas/FasL, TGFß1, TNF-α, and Th1/Th2 cytokines are not clearly delineated in HBV/HIV coinfection. METHODS: Levels of soluble Fas/FasL, TGFß1, TNF-α, and sPD-1/sPD-L1 as well as Th1 and Th2 cytokines were evaluated in the sera of HBV-monoinfected (n = 30) and HBV/HIV-coinfected (n = 15) patients and compared to levels in healthy controls (n = 20). RESULTS: HBV-monoinfected patients had significantly lower levels of the anti-inflammatory cytokine IL-4 (P < 0.05) and higher levels of apoptotic markers sFas, sFasL, and TGFß-1 (P < 0.001) compared to healthy controls. Coinfection with HIV was associated with higher levels of sFas, TNF-α, and sPD-L1 (P < 0.005), and higher levels of the pro-inflammatory cytokines IL-6, IL-8, and IL-12p70 (P < 0.05) compared to healthy controls. Patients with HBV infection had a unique biomarker clustering profile comprised of IFN-γ, IL12p70, IL-10, IL-6, and TNF-α that was distinct from the profile of the healthy controls, and the unique HIV/HBV profile comprised GM-CSF, IL-4, IL-2, IFN-γ, IL12p70, IL-7, IL-10, and IL-1ß. In HBV monoinfection a significant correlation between sFasL and PD1(r = 0.46, P = < 0.05) and between sFas and PDL1 (r = 0.48, P = <0.01) was observed. CONCLUSION: HBV-infected and HBV/HIV-coinfected patients have unique apoptosis and inflammatory biomarker profiles that distinguish them from each other and healthy controls. The utilization of those unique biomarker profiles for monitoring disease progression or identifying individuals who may benefit from novel immunotherapies such as anti-PD-L1 or anti-PD-1 checkpoint inhibitors appears promising and warrants further investigation.

Cure Strategies for Hepatitis B Virus: The Promise of Immunotherapy.

Chronic hepatitits B virus remains a public health challenge, infecting more than 240 million people globally and causing 600,000 deaths per year from end-stage liver disease and/or hepatocellular carcinoma. Current antiviral therapeutic agents are highly effective at blocking viral replication, but discontinuation of therapy prior to loss of hepatitis B surface antigen generally leads to relapse. New modalities that target host factors of viral persistence such as immune response pathway inhibition hold promise. Other experimental approaches may target virally related persistence factors, including covalently closed circular DNA. All these approaches will require creative new means of assessing proof of biology and proof of mechanism, particularly in the relevant compartment of liver tissue. Furthermore, it is likely to require combinations of modalities in defined patient populations to achieve optimal response. A precompetitive consortium approach may enable companies, regulators, and academic researchers to share best practices and evaluate preclinical and clinical pathways for these novel approaches.

Blood Aspergillus RNA is a promising alternative biomarker for invasive aspergillosis.

A critical challenge for the successful application of antifungal therapies for invasive aspergillosis (IA) is a lack of reliable biomarkers to assess early treatment response. Patients with proven or probable IA were prospectively enrolled, and serial blood samples were collected at 8 specified time points during 12-week antifungal therapy. Total nucleic acid was extracted from 2.5 ml blood and tested for Aspergillus-specific RNA by a pan-Aspergillus real-time nucleic acid sequence-based amplification (NASBA) assay. Serum 1, 3-ß-D-glucan (BG) and galactomannan (GM) were measured in parallel. Clinical outcome was evaluated at 6 and 12 weeks. Overall, 48/328 (14.6%) blood samples from 29/46 (63%) patients had positive NASBA detection at baseline and/or some point during the study. Positive NASBA results during the first 4 and 6 weeks of treatment are significantly associated with the 12-week outcome. Blood RNA load change during weeks 4-6 may be informative to predict outcome at 12 weeks. While independent of serum GM, the kinetic change of circulating Aspergillus RNA appears to be well correlated with that of BG on some patient individuals. Monitoring blood Aspergillus RNA during the first 4-6 weeks of antifungal treatment may help assess therapeutic response. Combination of circulating Aspergillus RNA and BG may be a useful adjunct to assess response.

Pseudomonas aeruginosa Bacteremic Patients Exhibit Nonprotective Antibody Titers Against Therapeutic Antibody Targets PcrV and Psl Exopolysaccharide.

BACKGROUND: The type 3 secretion protein PcrV and Psl exopolysaccharide are promising therapeutic antibody targets against Pseudomonas aeruginosa. We examined P. aeruginosa bloodstream infection (BSI) isolates for the ability to express PcrV and Psl and evaluated corresponding patient serum for active titers to these targets. METHODS: We identified 114 patients with acute P. aeruginosa BSI; 56 cases were accompanied by acute sera. Serum was evaluated for PcrV- and Psl-specific immunoglobulin G (IgG) and for cytotoxicity and opsonophagocytosis. Isolates were evaluated for susceptibility to antibiotics, expression of PcrV and Psl, and susceptibility to the anti-PcrV/Psl bispecific antibody and clinical candidate MEDI3902. RESULTS: In-hospital mortality for patients with P. aeruginosa BSI was 39%. A total of 26% of isolates were resistant to ≥3 antibiotic classes. Although PcrV and/or Psl were detected in 99% of isolates, a majority of patients lacked active titers to PcrV (100%) and Psl (98%). In addition, MEDI3902 was active against all tested isolates. CONCLUSIONS: A vast majority of P. aeruginosa BSI isolates express PcrV and Psl; however, patient sera most often lacked IgG and functionally active responses to these targets. These results suggest that therapies directed at PcrV and Psl could be a promising approach for combating P. aeruginosa bloodstream infections.

Epidemiology of Hepatitis C Virus: A Battle on New Frontiers.

The hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality in the United States and other parts of the world. The epidemiology of the disease is highly variable between and within countries, and strategies to deal with HCV identification and treatment must be tailored to the geographic location and the political and economic environment of the region. Although great strides have been made in improving HCV transmission risk in blood supply products, new challenges related to changing patterns of disease incidence continue to require fresh evaluation and new approaches to disease prevention.

Correlation between Circulating Fungal Biomarkers and Clinical Outcome in Invasive Aspergillosis.

Objective means are needed to predict and assess clinical response in patients treated for invasive aspergillosis (IA). We examined whether early changes in serum galactomannan (GM) and/or ß-D-glucan (BDG) can predict clinical outcomes. Patients with proven or probable IA were prospectively enrolled, and serial GM and BDG levels and GM optical density indices (GMI) were calculated twice weekly for 6 weeks following initiation of standard-of-care antifungal therapy. Changes in these biomarkers during the first 2 and 6 weeks of treatment were analyzed for associations with clinical response and survival at weeks 6 and 12. Among 47 patients with IA, 53.2% (25/47) and 65.9% (27/41) had clinical response by weeks 6 and 12, respectively. Changes in biomarkers during the first 2 weeks were associated with clinical response at 6 weeks (GMI, P = 0.03) and 12 weeks (GM+BDG composite, P = 0.05; GM, P = 0.04; GMI, P = 0.02). Changes in biomarkers during the first 6 weeks were also associated with clinical response at 6 weeks (GM, P = 0.05; GMI, P = 0.03) and 12 weeks (BDG+GM, P = 0.02; GM, P = 0.02; GMI, P = 0.01). Overall survival rates at 6 weeks and 12 weeks were 87.2% (41/47) and 79.1% (34/43), respectively. Decreasing biomarkers in the first 2 weeks were associated with survival at 6 weeks (BDG+GM, P = 0.03; BDG, P = 0.01; GM, P = 0.03) and at 12 weeks (BDG+GM, P = 0.01; BDG, P = 0.03; GM, P = 0.01; GMI, P = 0.007). Similar correlations occurred for biomarkers measured over 6 weeks. Patients with negative baseline GMI and/or persistently negative GMI during the first 2 weeks were more likely to have CR and survival. These results suggest that changes of biomarkers may be informative to predict and/or assess response to therapy and survival in patients treated for IA.